The blood vessels of the central nervous system are enveloped by a basement membrane surrounded by astrocyte spurs stretched toward the endothelial cell barrier (Risau, W., Nature 386, 671-674, 1997; Abbott, N. J., et al., Nat. Rev. Neurosci. 7, 41-53, 2006; Kim, J. H., et al., J. Biochem. Mol. Biol. 39, 339-345, 2006; Ballabh, P., et al., Neurobiol. Dis. 16, 1-13, 2004). The endothelial cell barrier has a highly selective permeability and plays an important role in regulating the homeostasis of the micro-environment in the brain. This structure is called the gliovascular interface (Abbott, N. J., et al., Nat. Rev. Neurosci. 7, 41-53, 2006). Structural change of the gliovascular interface is observed when a pathological status of the central nervous system, including ischemia or neuroglyoma develops. This structural change includes phenomena such as atrocytes falling apart from the blood vessel where abnormal angiogenesis occurs and where the blood leaks (Rich, J. N., and Bigner, D. D Nat. Rev. Drug Discov. 3, 430-446, 2004; Maher, E. A., Genes Dev. 15, 1311-1333, 2001; Lee, S. W., et al., Arch. Pharm. Res. 29, 265-275, 2006). Thus, the interaction between astrocytes and endothelial cells is a key factor for regulating the barrier in the gliovascular interface. However, the exact mechanism of regulating this interaction has not been fully explained.
According to recent reports, neovascularization in the central nervous system can be explained by two important mechanisms: angiogenesis and barriergenesis (Lee, S. W., et al., Nat. Med. 9, 900-906, 2003; Rieckmann, P. and Engelhardt, B Nat. Med. 9, 828-829, 2003; Park, J. A., et al., Ontogeny to Artificial Interfaces, pp. 41-59, 2006). Particularly, astroglial cells of the brain and retina under development recognize the hypoxia generated in neuroglial cells to induce angiogenesis (Risau, W., Nature 386, 671-674, 1997). The newly generated blood vessels become mature as development proceeds. Angiogenesis then stops and the endothelial cells of the blood vessels gain selective permeability via barriergenesis (Engelhardt, B., Cell Tissue Res. 314, 119-129, 2003; Riasu, W. and Wolburg, H. Trends Neurosci. 13, 174-178, 1990). A few previous studies have found that the endothelial cells and astrocytes interact to induce the maturation of blood vessels and maintain the matured blood vessels that have barrier characteristics in the gliovascular interface (Risau, W., Proc. Natl. Acad. Sci. U.S.A. 83, 3855-3859, 1986; Janzer, R. C. and Raff, M. C. Nature 325, 253-257, 1987; Laterra, J., et al., J. Cell Physiol. 144, 204-215, 1990; Zerlin, M. and Goldman, J. E. J. Comp Neurol. 387, 537-546, 1997). Astrocytes in the gliovascular interface have been known to play an important role in regulating the growth, stabilization and maturation of blood vessels. That is, the astrocytes regulate the expression and secretion of various factors needed to build a functional blood vessel (Risau, W., Proc. Natl. Acad. Sci. U.S.A. 83, 3855-3859, 1986; Yonezawa, T., et al., Glia 44, 190-204, 2003; Haseloff, R. F., et al., Cell Mol. Neurobiol. 25, 25-39, 2005; Chow, J., et al., Brain Res. Dev. Brain Res. 130, 123-132, 2001; West, H., et al., Development 132, 1855-1862, 2005). Under the influence of a local factor, endothelial cells of the blood vessel become tighter and form wider intercellular junctions.
The present inventors investigated gene expression in relation to oxygen regulation in astrocytes to study astrocyte-mediated signals involved in blood vessel maturation and confirmed that this mechanism is closely related to angiogenesis (Lee, S. W., et al., Nat. Med. 9, 900-906, 2003; Song, H. S., et al., Biochem. Biophys. Res. Commun. 290, 325-331, 2002). According to the previous study, the oxygen regulating gene (hyrac; PubMed Access No. AY800384 and DQ133462) separated from the astrocytes of the brain after the birth of a rat encodes meteorin protein (Nishino, J. et al., EMBO J. 23, 1998-2008, 2004). Particularly, meteorin is a secreted protein, which is expressed in non-differentiated neural precursor cells and radial glia. Meteorin indirectly promotes the axon extension in the presence of astrocytes. In this study, the indirect effect of meteorin on neurons is presumably attributed to environmental changes that provide a signal for nerve growth.
The present inventors completed this invention by confirming that meteorin is highly expressed in astrocytes of the brain and retina of a mouse in the late embryonic stage and right after birth. It is in particular highly detected in the astrocyte endfeet surrounding blood vessels, and promotes the expression of thrombospondin-1/-2 (TSP-1/-2) to inhibit angiogenesis and accelerate blood vessel maturation.